Tuesday, February 4, 2025
2/4/2025
Project Summary/Abstract Obesity is highly prevalent in the United States, yet available treatment options remain limited. The peptide hormone amylin, which reduces food intake and body weight, is thought to be a promising potential target for novel obesity treatments. As obesity is driven in part by overconsumption of highly palatable, rewarding foods, there is growing interest in examining how feeding-relevant signals such as amylin act at reward-relevant nuclei of the brain to control food intake. The ventral tegmental area (VTA) of the mesolimbic reward system is both physiologically and pharmacologically relevant for amylin-mediated suppression of food intake, but the behavioral and physiological mechanisms by which VTA amylin promotes negative energy balance remain unresolved. This proposal is designed to evaluate mechanisms by which VTA amylin signaling suppresses intake of particular dietary macronutrients to promote negative energy balance. Studies also further investigate sex differences in VTA amylin-mediated control of feeding and body weight, with particular focus on the influence of estradiol on the effects of VTA amylin receptor activation. Specific Aim I will test mechanisms by which VTA amylin signaling modulates dopamine signaling to suppress intake of particular dietary macronutrients. First, the hypothesis that VTA amylin receptor (AmyR) activation potently suppresses phasic dopamine in the nucleus accumbens core, another key mesolimbic nucleus, in response to intraoral fat will be evaluated with fast-scan cyclic voltammetry. We will also investigate the relative contribution of orosensory versus postingestive feedback to activation of VTA AmyR-expressing dopamine neurons. Further, we will use a Cre-dependent adeno-associated virus (AAV) to knock down AmyR expression in VTA dopamine neurons, and examine how this neuronal population contributes to endogenous control of energy balance by amylin. Specific Aim II addresses a critical gap in the literature by evaluating physiological and pharmacological relevance of VTA AmyR in control of palatable food intake and body weight in females, and will test the influence of estradiol on the energy balance effects of VTA AmyR signaling. We will also evaluate how estradiol alters expression of AmyR components in the VTA, thereby providing novel mechanistic insight into central interactions of estradiol and amylin in energy balance control. These studies build upon the PI’s previous K01 and R03 awards by investigating the neural and behavioral mechanisms by which mesolimbic amylin signaling promotes negative energy balance and will address new aspects of this area of research by providing deeper insight into the mechanisms by which VTA amylin signaling controls macronutrient intake as well as sex differences in these effects. Collectively, these studies will provide information on mechanisms of action by which amylin reduces food intake and promotes weight loss, which may in turn facilitate the development of more effective pharmacotherapies for treating obesity.
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